Non-insulin dependent and insulin-dependent diabetes (NIDD and IDD) are considered genetically and etiologically distinct entities; IDD is often equated with Type I (autoimmune) diabetes, while NIDD is thought to be non-autoimmune (Type II). However, both IDD and NIDD are found in some families. In families with an NIDD parent and an IDD proband (NIDD/IDD families), and primarily in those with more than one IDD child, we found that the IDD probands had a increased frequency of B44-DR4, a haplotype not associated with susceptibility to IDD. The IDD probands in these families also have an increased frequency of late ( > 15 years) age of onset of disease as compared to probands in IDD/IDD families or those with non-diabetic parents. These NIDD/IDD families may represent a form of diabetes (Type X) which can manifest as either NIDD or IDD, and might have a different etiology from "classical" IDD. The proposed studies address two types of questions: (i) Immunogenetic studies and studies on the pattern of occurrence of diabetes in NIDD/IDD and IDD/IDD families. These include the analysis of B44-DR4 association with the NIDD/IDD family pattern, and particularly with this pattern in families with more than one IDD sib, the behavior of this haplotype as a possible susceptibility factor for both NIDD and IDD, and the development of NIDD in siblings of the IDD proband in these families. (ii) Studies on potential etiologic factors and on the evolution of disease in NIDD/IDD families. These include cross-sectional evaluation of clinical parameters, as well as longitudinal studies of clinical, metabolic, and immunologic parameters. These include parameters such as sex, age at onset, weight history, and treatment history; acute-phase insulin response; and islet-cell and insulin antibodies. These combined studies will help to determine whether there is a "Type X" form of diabetes which can manifest as either NIDD or IDD and may be different in etiology from either or both the "classical" Type I and Type II. The identification of such a form of diabetes is significant in terms of both genetic counseling in affected families and the use of intervention strategies based on current assumption about the etiology of IDD; it will also be useful in conceiving and designing other intervention strategies.